A number of isoindoloindolone compounds have been described in the literature, especially in Tetrahedron 1993, 49 (1), 151-164, without any pharmacological activity being described for those compounds.
The compounds of the present invention are new and exhibit pharmacological characteristics that are very valuable in respect of melatoninergic receptors.
Numerous studies in the last ten years have demonstrated the key role of melatonin (N-acetyl-5-methoxytryptamine) in many physiopathological phenomena and in the control of circadian rhythm, but melatonin has a rather short half-life owing to the fact that it is rapidly metabolised. Great interest therefore lies in the possibility of making available to the clinician melatonin analogues that are metabolically more stable and have an agonist or antagonist character and of which the therapeutic effect may be expected to be superior to that of the hormone itself.
In addition to their beneficial action in respect of circadian rhythm disorders (J. Neurosurg. 1985, 63, pp. 321-341) and sleep disorders (Psychopharmacology, 1990, 100, pp. 222-226), ligands of the melatoninergic system have valuable pharmacological properties in respect of the central nervous system, especially anxiolytic and antipsychotic properties (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp. 264-272), and analgesic properties (Pharmacopsychiat., 1987, 20, pp. 222-223), and also for the treatment of Parkinson""s disease (J. Neurosurg. 1985, 63, pp. 321-341) and Alzheimer""s disease (Brain Research, 1990, 528, pp. 170-174). The compounds have also demonstrated activity in relation to certain cancers (Melatoninxe2x80x94Clinical Perspectives, Oxford University Press, 1988, pp. 164-165), ovulation (Science 1987, 227, pp. 714-720), diabetes (Clinical Endocrinology, 1986, 24, pp. 359-364), and in the treatment of obesity (International Journal of Eating Disorders, 1996, 20 (4), pp. 443-446).
Those various effects are exerted via the intermediary of specific melatonin receptors. Molecular biology studies have demonstrated the existence of a number of receptor sub-types that are capable of binding that hormone (Trends Pharmacol. Sci., 1995, 16, p. 50; WO 97 04094). It has been possible for some of those receptors to be located and characterised for different species, including mammals. In order to be able to understand the physiological functions of those receptors better, it is of great advantage to have available specific ligands. Moreover such compounds, by interacting selectively with one or another of those receptors, may be excellent medicaments for the clinician in the treatment of pathologies associated with the melatoninergic system, some of which have been mentioned above.
The compounds of the present invention, in addition to being new, exhibit a strong affinity for melatonin receptors and a significant selectivity for sites of the MT3 type.
The present invention relates more especially to the compounds of formula (I) 
wherein
R1, R2, R3, R4, R5, R6 and R8, which may be identical or different, each represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, an aryl-(C1-C6)alkyl group in which alkyl may be linear or branched, a hydroxy group, a linear or branched (C1-C6)alkoxy group, an aryl-(C1-C6)alkoxy group in which alkoxy may be linear or branched, a linear or branched (C1-C6)acyloxy group, an arylcarbonyloxy group, a carboxy-(C1-C6)alkyl group in which alkyl may be linear or branched, or a carboxy group,
R7 represents a hydrogen atom or a hydroxy group, a linear or branched (C1-C6)alkoxy group, an aryl-(C1-C6)alkoxy group in which alkoxy may be linear or branched, a linear or branched (C1-C6)acyloxy group or an arylcarbonyloxy group,
or one of the groups R1 to R8, together with another of the groups R1 to R8 adjacent to it, forms a (C1-C2)alkylenedioxy group,
to their optical isomers, where they exist, and to addition salts thereof with a pharmaceutically acceptable acid or base,
with the proviso:
that at least one of the groups R1 to R8 represents a hydroxy, a linear or branched (C1-C6)alkoxy, a linear or branched (C1-C6)acyloxy or an arylcarbonyloxy group,
and that the compounds of formula (I) are other than 1,3-dimethoxy-6H-isoindolo[2,1-a]indol-6-one.
xe2x80x9cArylxe2x80x9d is to be understood as phenyl, biphenyl, naphthyl or tetrahydronaphthyl, wherein each of those groups is optionally substituted by one or more identical or different atoms or groups selected from halogen atoms and linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)polyhaloalkyl, amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups), nitro, linear or branched (C1-C6)acyl and (C1-C2)alkylenedioxy.
Amongst the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulphonic, camphoric, oxalic acid.
Amongst the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine.
The invention relates also to a process for the preparation of the compounds of formula (I) which is characterised in that a compound of formula (II): 
wherein R1, R2, R3 and R4 are as defined for formula (I),
is reacted with N-bromosuccinimide to yield a compound of formula (III): 
wherein R1, R2, R3 and R4 are as defined hereinbefore,
which is reacted with triphenylphosphine to yield a compound of formula (IV): 
wherein R1, R2, R3 and R4 are as defined hereinbefore,
which is reacted with a compound of formula (V): 
wherein R5, R6, R7 and R8 are as defined for formula (I),
to yield a compound of formula (VI): 
wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined hereinbefore,
which is subjected to the action of a reducing agent to yield a compound of formula (VII): 
wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined hereinbefore,
which is then cyclised to yield a compound of formula (I), which is purified, if necessary, according to a conventional purification technique, is separated, if desired, into its optical isomers according to a conventional separation technique, and is converted, if desired, into addition salts with a pharmaceutically acceptable acid or base.
The compounds of the invention and the pharmaceutical compositions containing them have proved useful in the treatment of disorders of the melatoninergic system.
A pharmacological study of the compounds of the invention has in fact demonstrated that they are non-toxic, have a high selective affinity for melatonin receptors and have substantial activity in respect of the central nervous system and, in particular, they have been found to have therapeutic properties in respect of sleep disorders, anxiolytic, antipsychotic and analgesic properties and properties in respect of microcirculation, enabling it to be established that the compounds of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal affective disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jetlag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson""s disease, senile dementia, various disorders associated with normal or pathological ageing, migraine, memory losses, Alzheimer""s disease, and in cerebral circulation disorders. In another field of activity, it appears that the compounds of the invention can be used in the treatment of sexual dysfunctions, that they have ovulation-inhibiting and immunomodulating properties and that they are capable of being used in the treatment of cancers.
The compounds will preferably be used in the treatment of seasonal affective disorders, sleep disorders, cardiovascular pathologies, insomnia and fatigue due to jetlag, appetite disorders and obesity.
For example, the compounds will be used in the treatment of seasonal affective disorders and sleep disorders.
The present invention relates also to pharmaceutical compositions comprising a compound of formula (I) in combination with one or more pharmaceutically acceptable excipients.
Amongst the pharmaceutical compositions according to the invention there may be mentioned more especially those which are suitable for oral, parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration, especially tablets or dragees, sublingual tablets, sachets, paquets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels and drinkable or injectable ampoules.
The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication or possibly associated treatments, and ranges from 0.01 mg to 1 g per 24 hours in one or more administrations.